NO322800B1 - Heterocykliske sulfonamider, farmasoytiske preparater omfattende slike, anvendelse av disse for fremstilling av medikamenter for behandling eller forebygging av lidelser, fremstilling av disse samt anvendelse av disse for behandling av sykdommer. - Google Patents

Heterocykliske sulfonamider, farmasoytiske preparater omfattende slike, anvendelse av disse for fremstilling av medikamenter for behandling eller forebygging av lidelser, fremstilling av disse samt anvendelse av disse for behandling av sykdommer. Download PDF

Info

Publication number: NO322800B1
Authority: NO; Norway
Prior art keywords: methoxy; phenoxy; pyridine; pyrimidin; methyl
Prior art date: 1999-01-18

Application number

NO20013454A

Other languages

English (en)

Norwegian (no)

Other versions

NO20013454L (no

NO20013454D0 (no

Inventor

Hans Peter Wessel

Henri Ramuz

Volker Breu

Philippe Coassolo

Rolf Huber

Werner Neidhart

Sebastien Roux

Original Assignee

Hoffmann La Roche

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1999-01-18

Filing date

2001-07-12

Publication date

2006-12-11

2001-07-12 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

2001-07-12 Publication of NO20013454L publication Critical patent/NO20013454L/no

2001-07-12 Publication of NO20013454D0 publication Critical patent/NO20013454D0/no

2006-12-11 Publication of NO322800B1 publication Critical patent/NO322800B1/no

Links

-1 Heterocyclic sulfonamides Chemical class 0.000 title claims description 97
229940124530 sulfonamide Drugs 0.000 title claims description 23
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 12
238000004519 manufacturing process Methods 0.000 title claims description 10
239000003814 drug Substances 0.000 title claims description 8
201000010099 disease Diseases 0.000 title claims description 5
230000002265 prevention Effects 0.000 title claims description 5
238000002360 preparation method Methods 0.000 title description 28
229940079593 drug Drugs 0.000 title description 6
239000008194 pharmaceutical composition Substances 0.000 title 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 111
150000001875 compounds Chemical class 0.000 claims description 94
238000006243 chemical reaction Methods 0.000 claims description 46
239000002904 solvent Substances 0.000 claims description 35
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
PWSQPYYJRFUQNY-UHFFFAOYSA-N 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylic acid Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(O)=O)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 PWSQPYYJRFUQNY-UHFFFAOYSA-N 0.000 claims description 26
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 20
125000000217 alkyl group Chemical group 0.000 claims description 17
239000001257 hydrogen Substances 0.000 claims description 16
229910052739 hydrogen Inorganic materials 0.000 claims description 16
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
125000004093 cyano group Chemical group *C#N 0.000 claims description 14
150000003456 sulfonamides Chemical class 0.000 claims description 12
125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 10
150000002431 hydrogen Chemical class 0.000 claims description 10
150000003839 salts Chemical class 0.000 claims description 10
239000000654 additive Substances 0.000 claims description 9
239000003153 chemical reaction reagent Substances 0.000 claims description 8
USAZCYCMURFAHN-UHFFFAOYSA-N n-[2-(3-hydroxyphenyl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(O)C=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 USAZCYCMURFAHN-UHFFFAOYSA-N 0.000 claims description 8
TZGPRVZHYJHRJM-UHFFFAOYSA-N n-[2-(2-cyanopyridin-4-yl)-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C#N)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 TZGPRVZHYJHRJM-UHFFFAOYSA-N 0.000 claims description 7
DSPWOBHBGWPXJE-UHFFFAOYSA-N 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylic acid Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(O)=O)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 DSPWOBHBGWPXJE-UHFFFAOYSA-N 0.000 claims description 6
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
HWDVVFJLGKKDDY-UHFFFAOYSA-N n-[2-[2-(hydroxymethyl)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(CO)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 HWDVVFJLGKKDDY-UHFFFAOYSA-N 0.000 claims description 6
206010048554 Endothelial dysfunction Diseases 0.000 claims description 5
230000002159 abnormal effect Effects 0.000 claims description 5
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
230000008694 endothelial dysfunction Effects 0.000 claims description 5
125000000623 heterocyclic group Chemical group 0.000 claims description 5
JBMOXASJKXMRQK-UHFFFAOYSA-N methyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound C1=NC(C(=O)OC)=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(C)=CC=3)N=2)=C1 JBMOXASJKXMRQK-UHFFFAOYSA-N 0.000 claims description 5
MGOPRDLMTJAUDR-UHFFFAOYSA-N n-[2-[3-(2-hydroxyethoxy)phenyl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(OCCO)C=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 MGOPRDLMTJAUDR-UHFFFAOYSA-N 0.000 claims description 5
IPCRQNKALGQPEY-UHFFFAOYSA-N n-[6-methoxy-5-(2-methoxyphenoxy)-2-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-4-yl]pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C=2N=C(C)ON=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 IPCRQNKALGQPEY-UHFFFAOYSA-N 0.000 claims description 5
239000000825 pharmaceutical preparation Substances 0.000 claims description 5
230000006442 vascular tone Effects 0.000 claims description 5
BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 4
150000002148 esters Chemical class 0.000 claims description 4
JBOAZACHEBUCCG-UHFFFAOYSA-N ethyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound C1=NC(C(=O)OCC)=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(C)=CC=3)N=2)=C1 JBOAZACHEBUCCG-UHFFFAOYSA-N 0.000 claims description 4
FFIICJXAEMQRPV-UHFFFAOYSA-N ethyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound C1=NC(C(=O)OCC)=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(=CC=3)C(C)C)N=2)=C1 FFIICJXAEMQRPV-UHFFFAOYSA-N 0.000 claims description 4
LXNTVTQZKZHOQG-UHFFFAOYSA-N methyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound C1=NC(C(=O)OC)=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(=CC=3)C(C)C)N=2)=C1 LXNTVTQZKZHOQG-UHFFFAOYSA-N 0.000 claims description 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 3
JVISYACOKHFQLD-UHFFFAOYSA-N N'-hydroxy-4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboximidamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(=N)NO)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 JVISYACOKHFQLD-UHFFFAOYSA-N 0.000 claims description 3
ZDLIYCVDCFABIY-UHFFFAOYSA-N [3-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]phenyl] acetate Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(OC(C)=O)C=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 ZDLIYCVDCFABIY-UHFFFAOYSA-N 0.000 claims description 3
230000000996 additive effect Effects 0.000 claims description 3
125000003342 alkenyl group Chemical group 0.000 claims description 3
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
PTOBBLWJHXHHBN-UHFFFAOYSA-N n-[2-[2-(hydroxymethyl)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(CO)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 PTOBBLWJHXHHBN-UHFFFAOYSA-N 0.000 claims description 3
125000000335 thiazolyl group Chemical group 0.000 claims description 3
BUIBBWMIISPCPE-UHFFFAOYSA-N 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(N)=O)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 BUIBBWMIISPCPE-UHFFFAOYSA-N 0.000 claims description 2
125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
LEPZHONWBRDTIQ-UHFFFAOYSA-N n-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-oxo-1h-pyridin-4-yl)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(O)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 LEPZHONWBRDTIQ-UHFFFAOYSA-N 0.000 claims description 2
ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims description 2
125000004076 pyridyl group Chemical group 0.000 claims description 2
238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
125000005270 trialkylamine group Chemical group 0.000 claims description 2
FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 2
125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
DTVHASKEQAUBMN-UHFFFAOYSA-N N'-hydroxy-4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboximidamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(=N)NO)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 DTVHASKEQAUBMN-UHFFFAOYSA-N 0.000 claims 1
IHKAXUYWYVTCEJ-UHFFFAOYSA-N ethyl 2-[3-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]phenoxy]acetate Chemical compound CCOC(=O)COC1=CC=CC(C=2N=C(OC)C(OC=3C(=CC=CC=3)OC)=C(NS(=O)(=O)C=3N=CC(C)=CC=3)N=2)=C1 IHKAXUYWYVTCEJ-UHFFFAOYSA-N 0.000 claims 1
ILWORCFVIJMBEH-UHFFFAOYSA-N n-[2-[2-(2-hydroxyethoxy)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methyl-1,3-thiazole-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(OCCO)N=CC=2)OC)=C1NS(=O)(=O)C1=NC=C(C)S1 ILWORCFVIJMBEH-UHFFFAOYSA-N 0.000 claims 1
IQCNZVLOUOHMKZ-UHFFFAOYSA-N n-[2-[2-(2-hydroxyethoxy)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(OCCO)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 IQCNZVLOUOHMKZ-UHFFFAOYSA-N 0.000 claims 1
GBVBKQUMFUNJSX-UHFFFAOYSA-N n-[2-[2-(methanesulfonamidomethyl)pyridin-4-yl]-6-methoxy-5-(2-methoxyphenoxy)pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(CNS(C)(=O)=O)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 GBVBKQUMFUNJSX-UHFFFAOYSA-N 0.000 claims 1
WDTDILVDYHGPTR-UHFFFAOYSA-N n-[[4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-propan-2-ylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridin-2-yl]methyl]acetamide Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(CNC(C)=O)N=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C(C)C)C=N1 WDTDILVDYHGPTR-UHFFFAOYSA-N 0.000 claims 1
239000007787 solid Substances 0.000 description 127
238000001819 mass spectrum Methods 0.000 description 112
239000000047 product Substances 0.000 description 97
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 71
239000000243 solution Substances 0.000 description 47
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
239000000203 mixture Substances 0.000 description 40
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
239000011734 sodium Substances 0.000 description 34
239000012044 organic layer Substances 0.000 description 33
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
235000019439 ethyl acetate Nutrition 0.000 description 29
239000000460 chlorine Substances 0.000 description 27
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
239000007858 starting material Substances 0.000 description 22
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
238000004809 thin layer chromatography Methods 0.000 description 21
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
238000004458 analytical method Methods 0.000 description 19
239000011541 reaction mixture Substances 0.000 description 14
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
238000001704 evaporation Methods 0.000 description 13
230000008020 evaporation Effects 0.000 description 13
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
239000013078 crystal Substances 0.000 description 12
238000000034 method Methods 0.000 description 11
238000010898 silica gel chromatography Methods 0.000 description 11
239000000725 suspension Substances 0.000 description 11
238000012360 testing method Methods 0.000 description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
238000011176 pooling Methods 0.000 description 10
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
125000004453 alkoxycarbonyl group Chemical group 0.000 description 9
RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 9
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
229910052708 sodium Inorganic materials 0.000 description 9
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
230000027455 binding Effects 0.000 description 8
108050009340 Endothelin Proteins 0.000 description 7
102000002045 Endothelin Human genes 0.000 description 7
239000002585 base Substances 0.000 description 7
210000004027 cell Anatomy 0.000 description 7
ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
101800004490 Endothelin-1 Proteins 0.000 description 6
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
241000700159 Rattus Species 0.000 description 6
239000000872 buffer Substances 0.000 description 6
230000008878 coupling Effects 0.000 description 6
238000010168 coupling process Methods 0.000 description 6
238000005859 coupling reaction Methods 0.000 description 6
MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 6
230000000694 effects Effects 0.000 description 6
239000010410 layer Substances 0.000 description 6
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
229910000104 sodium hydride Inorganic materials 0.000 description 6
238000003756 stirring Methods 0.000 description 6
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PAAPPCPERPUATR-UHFFFAOYSA-N phenacyl 4-[4-methoxy-5-(2-methoxyphenoxy)-6-[(5-methylpyridin-2-yl)sulfonylamino]pyrimidin-2-yl]pyridine-2-carboxylate Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2C=C(N=CC=2)C(=O)OCC(=O)C=2C=CC=CC=2)OC)=C1NS(=O)(=O)C1=CC=C(C)C=N1 PAAPPCPERPUATR-UHFFFAOYSA-N 0.000 description 1
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CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
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LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Medicinal Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Pulmonology (AREA)
Hematology (AREA)
Diabetes (AREA)
Immunology (AREA)
Ophthalmology & Optometry (AREA)
Urology & Nephrology (AREA)
Child & Adolescent Psychology (AREA)
Gynecology & Obstetrics (AREA)
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Biomedical Technology (AREA)
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Reproductive Health (AREA)
Obesity (AREA)
Gastroenterology & Hepatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Pyridine Compounds (AREA)
Hydrogenated Pyridines (AREA)

NO20013454A 1999-01-18 2001-07-12 Heterocykliske sulfonamider, farmasoytiske preparater omfattende slike, anvendelse av disse for fremstilling av medikamenter for behandling eller forebygging av lidelser, fremstilling av disse samt anvendelse av disse for behandling av sykdommer. NO322800B1 (no)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
EP99100784		1999-01-18
PCT/EP2000/000103 WO2000042035A1 (fr)	1999-01-18	2000-01-10	4-(heterocyclysulfonamido)-5-methoxy-6-(2-methoxyphenoxy)-2-phenyle ou pyridylpyrimidines faisant office d'antagonistes des recepteurs de l'endotheline

Publications (3)

Publication Number	Publication Date
NO20013454L NO20013454L (no)	2001-07-12
NO20013454D0 NO20013454D0 (no)	2001-07-12
NO322800B1 true NO322800B1 (no)	2006-12-11

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ID=8237359

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
NO20013454A NO322800B1 (no)	1999-01-18	2001-07-12	Heterocykliske sulfonamider, farmasoytiske preparater omfattende slike, anvendelse av disse for fremstilling av medikamenter for behandling eller forebygging av lidelser, fremstilling av disse samt anvendelse av disse for behandling av sykdommer.

Country Status (31)

Country	Link
US (1)	US6242601B1 (fr)
EP (1)	EP1149091B1 (fr)
JP (1)	JP3983477B2 (fr)
KR (1)	KR100478797B1 (fr)
CN (1)	CN1340049A (fr)
AR (1)	AR029879A1 (fr)
AT (1)	ATE389648T1 (fr)
AU (1)	AU763112B2 (fr)
BR (1)	BR0007595A (fr)
CA (1)	CA2359363C (fr)
CO (1)	CO5150187A1 (fr)
CZ (1)	CZ20012546A3 (fr)
DE (1)	DE60038365D1 (fr)
ES (1)	ES2301476T3 (fr)
GC (1)	GC0000248A (fr)
HR (1)	HRP20010515A2 (fr)
HU (1)	HUP0200021A3 (fr)
IL (2)	IL144055A0 (fr)
MA (1)	MA27124A1 (fr)
MY (1)	MY121136A (fr)
NO (1)	NO322800B1 (fr)
NZ (1)	NZ512662A (fr)
PE (1)	PE20001421A1 (fr)
PL (1)	PL350093A1 (fr)
RU (1)	RU2224757C2 (fr)
TR (1)	TR200102071T2 (fr)
TW (1)	TWI284642B (fr)
UY (1)	UY25904A1 (fr)
WO (1)	WO2000042035A1 (fr)
YU (1)	YU50001A (fr)
ZA (1)	ZA200105279B (fr)

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US20080300281A1 (en) *	1997-12-22	2008-12-04	Jacques Dumas	Inhibition of p38 Kinase Activity Using Aryl and Heteroaryl Substituted Heterocyclic Ureas
US7329670B1 (en)	1997-12-22	2008-02-12	Bayer Pharmaceuticals Corporation	Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
US7517880B2 (en)	1997-12-22	2009-04-14	Bayer Pharmaceuticals Corporation	Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
US20080269265A1 (en) *	1998-12-22	2008-10-30	Scott Miller	Inhibition Of Raf Kinase Using Symmetrical And Unsymmetrical Substituted Diphenyl Ureas
EP1140840B1 (fr) *	1999-01-13	2006-03-22	Bayer Pharmaceuticals Corp.	Diphenylurees a substituants -g(v)-carboxyaryles, inhibitrices de kinase raf
ME00275B (fr)	1999-01-13	2011-02-10	Bayer Corp	DIPHENYLUREES A SUBSTITUANTS ω-CARBOXYARYLES, INHIBITRICES DE KINASE RAF
US7928239B2 (en)	1999-01-13	2011-04-19	Bayer Healthcare Llc	Inhibition of RAF kinase using quinolyl, isoquinolyl or pyridyl ureas
EP1158985B1 (fr)	1999-01-13	2011-12-28	Bayer HealthCare LLC	DIPHENYLE UREES A SUBSTITUTION OMEGA-CARBOXY ARYLE EN TANT QU'INHIBITEURS DE LA KINASE p38
US8124630B2 (en)	1999-01-13	2012-02-28	Bayer Healthcare Llc	ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US6417360B1 (en) *	1999-03-03	2002-07-09	Hoffmann-La Roche Inc.	Heterocyclic sulfonamides
MY140724A (en)	2000-07-21	2010-01-15	Actelion Pharmaceuticals Ltd	Novel arylethene-sulfonamides
AU2002227984B8 (en) *	2000-12-18	2007-01-04	Actelion Pharmaceuticals Ltd.	Novel sulfamides and their use as endothelin receptor antagonists
US7235576B1 (en)	2001-01-12	2007-06-26	Bayer Pharmaceuticals Corporation	Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7371763B2 (en) *	2001-04-20	2008-05-13	Bayer Pharmaceuticals Corporation	Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
WO2003047579A1 (fr) *	2001-12-03	2003-06-12	Bayer Pharmaceuticals Corporation	Composes de type uree aryle combines a d'autres agents cytostatiques ou cytotoxiques et servant a traiter des cancers humains
WO2003068229A1 (fr)	2002-02-11	2003-08-21	Bayer Pharmaceuticals Corporation	N-oxydes de pyridine, de quinoline, et d'isoquinoline en tant qu'inhibiteurs de kinase
SI1478358T1 (sl)	2002-02-11	2013-09-30	Bayer Healthcare Llc	Sorafenib tozilat za zdravljenje bolezni, značilnih po abnormalni angiogenezi
US20040023961A1 (en) *	2002-02-11	2004-02-05	Bayer Corporation	Aryl ureas with raf kinase and angiogenisis inhibiting activity
ATE529406T1 (de) *	2002-02-11	2011-11-15	Bayer Healthcare Llc	Aryl-harnstoffe als kinase inhibitoren
CA2507334C (fr) *	2002-12-02	2013-05-07	Actelion Pharmaceuticals Ltd.	Pyrimidine-sulfamides et leur utilisation comme antagoniste du recepteur d'endotheline
US7269460B2 (en) *	2003-02-28	2007-09-11	Medtronic, Inc.	Method and apparatus for evaluating and optimizing ventricular synchronization
US7557129B2 (en)	2003-02-28	2009-07-07	Bayer Healthcare Llc	Cyanopyridine derivatives useful in the treatment of cancer and other disorders
EP1636585B2 (fr)	2003-05-20	2012-06-13	Bayer HealthCare LLC	Diaryl-urees presentant une activite d'inhibition des kinases
EP1663978B1 (fr)	2003-07-23	2007-11-28	Bayer Pharmaceuticals Corporation	Omega-carboxyaryldiphenyluree fluoro-subtituee pour le traitement et la prevention de maladies et d'etats pathologiques
EP1595880A1 (fr) *	2004-05-13	2005-11-16	Speedel Pharma AG	Formes crystallines d'un pyridinylsulphonamide et leur utilisation comme antagonistes du récepteur de l'endothéline
CR9465A (es) *	2005-03-25	2008-06-19	Surface Logix Inc	Compuestos mejorados farmacocineticamente
SG174050A1 (en) *	2006-04-13	2011-09-29	Actelion Pharmaceuticals Ltd	Endothelin receptor antagonists for early stage idiopathic pulmonary fibrosis
KR20090020559A (ko)	2006-05-29	2009-02-26	니콕스 에스. 에이.	엔도셀린 수용체 길항제로서의 질화 헤테로시클릭 화합물
AR062501A1 (es)	2006-08-29	2008-11-12	Actelion Pharmaceuticals Ltd	Composiciones terapeuticas
MX2010001837A (es)	2007-08-17	2010-03-10	Actelion Pharmaceuticals Ltd	Derivados de 4-pirimidinasulfamida.
EP3205649B1 (fr) *	2014-11-21	2021-02-24	Daikin Industries, Ltd.	Carbonate cyclique fluoré insaturé et son procédé de production
CN109260164A (zh) *	2018-10-07	2019-01-25	威海贯标信息科技有限公司	一种阿伏生坦片剂组合物
CN112778215B (zh) *	2021-01-29	2023-06-20	中国医科大学	2-甲氧基苯氧基嘧啶类抗肿瘤化合物及其制备方法和应用
CN112898208B (zh) *	2021-01-29	2023-06-20	中国医科大学	苯基嘧啶胺类抗肿瘤化合物及其制备方法和应用
JP7820522B2 (ja)	2021-12-17	2026-02-25	ネクセラファーマ株式会社	クラゾセンタン二ナトリウム塩、その製造及びそれを含有する医薬組成物

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CA2162630C (fr) *	1994-11-25	2007-05-01	Volker Breu	Sulfonamides
US5837708A (en)	1994-11-25	1998-11-17	Hoffmann-La Roche Inc.	Sulphonamides
WO1996016963A1 (fr) *	1994-11-25	1996-06-06	F. Hoffmann-La Roche Ag	Sulfonamides et leur utilisation comme medicaments
TW313568B (fr) *	1994-12-20	1997-08-21	Hoffmann La Roche
JP3087968B2 (ja) *	1995-12-20	2000-09-18	山之内製薬株式会社	アリールエテンスルホンアミド誘導体及びその医薬組成物

2000
- 2000-01-07 TW TW089100181A patent/TWI284642B/zh not_active IP Right Cessation
- 2000-01-10 AU AU26630/00A patent/AU763112B2/en not_active Ceased
- 2000-01-10 CA CA002359363A patent/CA2359363C/fr not_active Expired - Fee Related
- 2000-01-10 HU HU0200021A patent/HUP0200021A3/hu unknown
- 2000-01-10 NZ NZ512662A patent/NZ512662A/en unknown
- 2000-01-10 TR TR2001/02071T patent/TR200102071T2/xx unknown
- 2000-01-10 AT AT00904889T patent/ATE389648T1/de not_active IP Right Cessation
- 2000-01-10 RU RU2001122114/04A patent/RU2224757C2/ru not_active IP Right Cessation
- 2000-01-10 BR BR0007595-7A patent/BR0007595A/pt not_active Application Discontinuation
- 2000-01-10 KR KR10-2001-7008996A patent/KR100478797B1/ko not_active Expired - Fee Related
- 2000-01-10 IL IL14405500A patent/IL144055A0/xx not_active IP Right Cessation
- 2000-01-10 CN CN00803754A patent/CN1340049A/zh active Pending
- 2000-01-10 YU YU50001A patent/YU50001A/sh unknown
- 2000-01-10 WO PCT/EP2000/000103 patent/WO2000042035A1/fr not_active Ceased
- 2000-01-10 HR HR20010515A patent/HRP20010515A2/hr not_active Application Discontinuation
- 2000-01-10 EP EP00904889A patent/EP1149091B1/fr not_active Expired - Lifetime
- 2000-01-10 PL PL00350093A patent/PL350093A1/xx not_active Application Discontinuation
- 2000-01-10 DE DE60038365T patent/DE60038365D1/de not_active Expired - Lifetime
- 2000-01-10 ES ES00904889T patent/ES2301476T3/es not_active Expired - Lifetime
- 2000-01-10 JP JP2000593603A patent/JP3983477B2/ja not_active Expired - Lifetime
- 2000-01-10 CZ CZ20012546A patent/CZ20012546A3/cs unknown
- 2000-01-13 US US09/482,810 patent/US6242601B1/en not_active Expired - Fee Related
- 2000-01-13 PE PE2000000025A patent/PE20001421A1/es not_active Application Discontinuation
- 2000-01-14 CO CO00001821A patent/CO5150187A1/es unknown
- 2000-01-14 AR ARP000100159A patent/AR029879A1/es unknown
- 2000-01-14 MY MYPI20000124A patent/MY121136A/en unknown
- 2000-01-14 UY UY25904A patent/UY25904A1/es unknown
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2001
- 2001-06-26 ZA ZA200105279A patent/ZA200105279B/en unknown
- 2001-06-28 IL IL144055A patent/IL144055A/en unknown
- 2001-07-12 NO NO20013454A patent/NO322800B1/no unknown
- 2001-07-17 MA MA26270A patent/MA27124A1/fr unknown

Also Published As

Publication number	Publication date
IL144055A (en)	2007-07-24
RU2224757C2 (ru)	2004-02-27
NZ512662A (en)	2003-11-28
TR200102071T2 (tr)	2002-03-21
JP2002534518A (ja)	2002-10-15
EP1149091A1 (fr)	2001-10-31
WO2000042035A1 (fr)	2000-07-20
CO5150187A1 (es)	2002-04-29
BR0007595A (pt)	2001-10-16
GC0000248A (en)	2006-11-01
PL350093A1 (en)	2002-11-04
MA27124A1 (fr)	2005-01-03
EP1149091B1 (fr)	2008-03-19
IL144055A0 (en)	2002-04-21
ES2301476T3 (es)	2008-07-01
US6242601B1 (en)	2001-06-05
KR20010094746A (ko)	2001-11-01
CA2359363A1 (fr)	2000-07-20
ZA200105279B (en)	2002-10-07
CZ20012546A3 (cs)	2001-12-12
HUP0200021A2 (hu)	2002-05-29
MY121136A (en)	2005-12-30
CN1340049A (zh)	2002-03-13
AU763112B2 (en)	2003-07-10
YU50001A (sh)	2004-03-12
CA2359363C (fr)	2006-03-14
KR100478797B1 (ko)	2005-03-24
DE60038365D1 (en)	2008-04-30
PE20001421A1 (es)	2000-12-18
HRP20010515A2 (en)	2003-06-30
HUP0200021A3 (en)	2003-01-28
NO20013454L (no)	2001-07-12
AR029879A1 (es)	2003-07-23
JP3983477B2 (ja)	2007-09-26
NO20013454D0 (no)	2001-07-12
UY25904A1 (es)	2001-07-31
AU2663000A (en)	2000-08-01
ATE389648T1 (de)	2008-04-15
TWI284642B (en)	2007-08-01

Publication	Publication Date	Title
NO322800B1 (no)	2006-12-11	Heterocykliske sulfonamider, farmasoytiske preparater omfattende slike, anvendelse av disse for fremstilling av medikamenter for behandling eller forebygging av lidelser, fremstilling av disse samt anvendelse av disse for behandling av sykdommer.
JP4245130B2 (ja)	2009-03-25	新規なスルファミド類
CZ187497A3 (en)	1997-10-15	Sulfonamide derivative, process of its preparation and use
JP4769460B2 (ja)	2011-09-07	新規スルファミド類
AU2002212171B2 (en)	2006-12-14	Arylalkane-sulfonamides having endothelin-antagonist activity
AU2002212171A1 (en)	2002-06-20	Arylalkane-sulfonamides having endothelin-antagonist activity
EP1309564B1 (fr)	2006-06-14	Nouveaux sulfonamides arylethene
JP3488203B2 (ja)	2004-01-19	４−ヘテロシクリルスルホンアミジル−６−メトキシ−５−（２−メトキシ−フェノキシ）−２−ピリジル−ピリミジン誘導体、その製造方法及びエンドセリン受容体アンタゴニストとしての使用
AU2001281970A1 (en)	2002-05-02	Arylethene-sulfonamides, their preparation and their use as endothelin antagonists
AU2005303435A1 (en)	2006-05-18	Sulfamides as endothelin receptor antagonists for the treatment of cardiovascular diseases
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